2) SUMMARY OF WORK:PURPOSE: SIX years ago, I proposed a new model of the immune system (the Danger model) based on the assumption that the immune system?s function is to discriminate between dangerous and harmless things rather than self and non-self. Because this model has tremendous implications for such subjects as cancer, transplantation, neonatal vaccines, parasitology, and autoimmunity, we have been testing its basic premises and its applicability in several areas.RESULTS FROM THE PAST YEAR:1) TESTING THE BASIC PREMISE OF THE DANGER MODEL: Danger signals from injured tissues initiate immune responses. We found that 1) necrotic but not apoptotic cells can induce activation of dendritic cells in vitro and in vivo2) molecules secreted by virus infected cells, such as IFNalpha, can also induce dendritic cell activation3) these Danger signals can be used as adjuvants to elicit an immune response in vivo against the protein antigen, OVA4) Danger signals from exogenous sources, such as bacteria, induce apoptotic death of dendritic cells, whereas natural endogenous alarm signals do not.2) TRANSPLANTATION:A) orthotopic liver transplants:1)Livers transplanted across major histocompatibility barriers are accepted. With time, some of the recipients become tolerant of donor MHC class I molecules, as assayed by CTL activity, but not of donor MHC class II, measured in a proliferation assay.2) livers transplanted across a minor H barrier (such as male to female) induce deletion of the responding cells. B) Skin grafts to immuno-incompetent mice.1) donor T cells from a transplanted skin can remain viable and active for months after the transplant. If the graft is removed, the T cells nevertheless remain in the recipient nodes for weeks. These donor T cells can serve as a source of antigen to prime newly entering mature T Cells to induce rejection of the graft. They can also traffic to the thymus of the recipient and induce tolerance of newly developing T cells2) T cells maturing in an animal carrying a long-healed skin graft nevertheless reject that graft, showing that the T cells do not exit the thymus in a tolerizable only state. These data contradict all known models of central and peripheral tolerance. When tested by a sensitive PCR-based method, we found that the ?healed" skin grafts were not completely healed but continued to produce a number of molecules involved in cellular stress and/or healing. 3) T cells maturing in an animal carrying a long healed heart graft do not reject the graft, showing that the presence of "foreign" antigen does not elicit a rejection response in the absence of alarm signals.